Belzutifan Receives FDA Approval for Kidney Cancer Treatment
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In patients previously treated with immunotherapy (an anti-PD-1 or anti-PD-L1 antibody) and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI), whose renal cell carcinoma (RCC) subsequently progressed, belzutifan (Welireg, Merck & Co., Inc.) received FDA approval on December 14, 2023.
Kidney cancer is among the 10 most common cancers worldwide, accounting for approximately 2% of all cancers diagnosed. Its most common subtype is renal (kidney) cell carcinoma, which accounts for 90% of these cases.
2020 Turkey Cancer Statistics show that kidney cancer was the 15th most common cancer in Turkey, with 5,125 new cases annually. In the same year, 1,965 deaths from kidney cancer were reported, and the number of people living with the disease (5-year prevalence) was recorded as 14,172.
What Is Belzutifan, and How Does It Work?
Belzutifan is a new-generation cancer drug that acts as a hypoxia-inducible factor inhibitor (HIF inhibitor).
Welireg, which contains belzutifan, had previously been approved in August 2021 for von Hippel-Lindau (VHL) disease –associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) in adults who did not require immediate surgery.
The 2019 Nobel Prize in Medicine was awarded for research explaining how cells sense the availability of oxygen and adapt to low oxygen levels (hypoxia). These mechanisms are also critical to the rapid growth of tumor cells, because tumors need to adapt to surrounding tissues in order to grow and spread.
Belzutifan's mechanism of action specifically targets a protein called hypoxia-inducible factor 2 alpha (HIF-2α). Normally, cells initiate a range of adaptive mechanisms through the HIF-1α protein when oxygen levels are low. Chief among these is increasing production of the hormone erythropoietin (EPO), which raises blood cell numbers and thereby allows more oxygen to be carried to tissues. Tumor cells, however, can exploit this mechanism to promote the formation of additional blood vessels (angiogenesis) needed for rapid growth, supporting tumor nourishment and growth.
The illustration presents a diagram of belzutifan's effects on intracellular mechanisms. Under normal conditions (normoxia), proline hydroxylase enzymes in cells hydroxylate HIF-2α (hypoxia-inducible factor 2 alpha), allowing the VHL protein (von Hippel-Lindau tumor suppressor) to bind HIF-2α and promote its proteasomal degradation. With VHL dysfunction, however (shown as defective VHL or pVHL), HIF-2α remains stable and enters the cell nucleus. There it combines with HIF-1β, binds hypoxia-response elements, and regulates gene expression in response to oxygen deficiency (hypoxia or pseudohypoxia). This promotes tumor cell proliferation (multiplication), survival, metastasis (spread), and the formation of new blood vessels (angiogenesis).
Belzutifan acts in this mechanism by preventing HIF-2α stabilization and entry into the nucleus, suppressing the tumor cells' response to oxygen deficiency and the resulting processes that contribute to tumor growth. It is therefore used as an effective therapeutic agent in advanced RCC.
The illustration also indicates that belzutifan is effective against tumor growth and spread by preventing tumor cell proliferation, survival, and metastasis. This suggests that it may play an important role in cancer treatment by interfering with processes that nourish tumors, such as angiogenesis.
FDA Approval Based on the LITESPARK-005 Study
Efficacy was evaluated in LITESPARK-005, an open-label, randomized study enrolling 746 patients with unresectable, locally advanced or metastatic clear-cell RCC that had progressed after both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF-TKI.
Patients were randomized 1:1 to receive belzutifan 120 mg or everolimus 10 mg once daily. Randomization was stratified by International Metastatic RCC Database Consortium risk category and the number of prior VEGF-TKIs.
The main efficacy outcome measures were progression-free survival (PFS) assessed by blinded independent central review, and overall survival.
Results
- Patients treated with belzutifan had significantly better progression-free survival (PFS) than those treated with everolimus.
- Belzutifan reduced the risk of disease progression by 25% compared with everolimus. The confidence interval (95% CI: 0.63, 0.90) indicates a statistically significant improvement.
- Median progression-free survival was similar in both treatment groups, at approximately 5.6 months in each.
- Although overall survival data were not fully mature, no unfavorable trend was observed in the 59% of deaths reported so far.
- Analyses of patient-reported symptoms and functioning indicate that belzutifan was better tolerated than everolimus.
- Belzutifan treatment was found to have a statistically strong effect (one-sided p-value=0.0008).
The most common adverse effects in patients receiving belzutifan (occurring in more than 25%) were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase.
The recommended belzutifan dose is 120 mg taken orally once daily until disease progression or unacceptable toxicity.
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